CFO.selectmtd {CFO}

Select the maximum tolerated dose (MTD) for the real single-drug trial

Description

Select the maximum tolerated dose (MTD) when the real single-drug trial is completed

Usage

CFO.selectmtd(target, npts, ntox, 
       prior.para = list(alp.prior = target, bet.prior = 1 - target), 
       cutoff.eli = 0.95, early.stop = 0.95, verbose = TRUE)

Arguments

target

the target DLT rate.

npts

a vector containing the number of patients treated at each dose level.

ntox

a vector containing the number of patients who experienced DLT at each dose level.

prior.para

the prior parameters for a beta distribution, where set as list(alp.prior = target, bet.prior = 1 - target) by default, alp.prior and bet.prior represent the parameters of the prior distribution for the true DLT rate at any dose level. This prior distribution is specified as Beta(alpha.prior, beta.prior).

cutoff.eli

the cutoff to eliminate overly toxic doses for safety. We recommend the default value of cutoff.eli = 0.95 for general use.

early.stop

the threshold value for early stopping. The default value early.stop = 0.95 generally works well.

verbose

set verbose=TRUE to return more details of the results.

Details

CFO.selectmtd() selects the MTD based on isotonic estimates of toxicity probabilities. CFO.selectmtd() selects as the MTD dose j^*, for which the isotonic estimate of the DLT rate is closest to the target. If there are ties, we select from the ties the highest dose level when the estimate of the DLT rate is smaller than the target, or the lowest dose level when the estimate of the DLT rate is greater than the target. The isotonic estimates are obtained by the pooled-adjacent-violators algorithm (PAVA).

Value

CFO.selectmtd() returns

• target: the target DLT rate.

• MTD: the selected MTD. MTD = 99 indicates that all tested doses are overly toxic.

• p_est: the isotonic estimate of the DLT probablity at each dose and associated 95\% credible interval. p_est = NA if all tested doses are overly toxic.

• p_overdose: the probability of overdosing defined as Pr(toxicity > \code{target}|data). p_overdose = NA if all tested doses are overly toxic.

Note

The MTD selection and dose escalation/de-escalation rule are two independent components of the trial design. Isotonic regression is employed to select the MTD after the completion of the trial. When appropriate, another dose selection procedure (e.g., based on a fitted logistic model) can be used to select the MTD after the completion of the trial using the CFO-type design.

Author(s)

Jialu Fang, Wenliang Wang, and Guosheng Yin

References

Jin H, Yin G (2022). CFO: Calibration-free odds design for phase I/II clinical trials. Statistical Methods in Medical Research, 31(6), 1051-1066.
Bril G, Dykstra R, Pillers C, Robertson T (1984). Algorithm AS 206: Isotonic regression in two independent variables. Journal of the Royal Statistical Society. Series C (Applied Statistics), 33(3), 352–357.
Fang J, Yin G (2024). Fractional accumulative calibration‐free odds (f‐aCFO) design for delayed toxicity in phase I clinical trials. Statistics in Medicine.

Examples

### select the MTD for the CFO-type single-drug trial
n <- c(3,3,27,3,0,0,0)
y <- c(0,0,4,2,0,0,0)
selmtd <- CFO.selectmtd(target=0.2, npts=n, ntox=y)
summary(selmtd)
plot(selmtd)